The value of urinary gonadotropins in the diagnosis of central precocious puberty: a meta-analysis

Background The gonadotropin-releasing hormone (GnRH) stimulation test is time-consuming, invasive, and costly. However, it is the diagnostic gold standard for central precocious puberty (CPP), which in girls is defined as the onset of secondary sexual characteristics before the age of 8 years accompanied by breast buds, accelerated growth, and advanced bone age. This meta-analysis was performed to compare the diagnostic value of urinary gonadotropins and the GnRH stimulation test for CPP. Methods We searched six databases for relevant literature. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we estimated the sensitivity, specificity, area under the summary receiver operating characteristic curve (AUC), and publication bias. Results Six eligible trials fulfilled the inclusion criteria. In the meta-analysis of urinary luteinizing hormone (ULH), after excluding the data of one study, we obtained an AUC of 0.90 (sensitivity = 0.81, specificity = 0.85). The meta-analysis of the ULH to urinary follicle-stimulating hormone (UFSH) ratio revealed an AUC of 0.8116 (sensitivity = 0.79, specificity = 0.84). Conclusion Both the ULH level and ULH:UFSH ratio are effective and available approaches for CPP diagnosis. Trial Registration INPLASY 2021120076. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-022-03481-1.

3.2 Spearman correlation analysis of serum Gn and UGn before and after Gn-releasing hormone (GnRH) stimulation test 3.2.1 Correlation between basic serum Gn and UGn in MU1 (UGn1) and UGn in MU2 (UGn2) There were strong correlations between the basic serum LH level and the LH level in MU1 and MU2 (r = 0.574 and r = 0.569, respectively; both P < 0.01) and weaker correlations between the serum basal FSH level and the FSH level in MU1 and MU2 (r = 0.419 and r = 0.280, respectively; both P < 0.01).

Correlation between total 4-hour UGn and serum Gn peak after GnRH stimulation test
The correlations of LH and FSH between the 4-hour and peak concentrations were 0.719 and 0.403, respectively (both P < 0.01), indicating a strong correlation for both.
3.2.4 Correlation between serum LH:FSH ratio and 4-hour ULH:UFSH ratio after GnRH stimulation test The correlation between these values was 0.591 (P < 0.01), exhibiting a strong correlation.

Comparison of hormone levels among Tanner stages II, III, and IV
The serum basal Gn, UGn1, UGn2, serum Gn peak, and LH:FSH ratio after the GnRH stimulation test as well as the UGn and 4-hour ULH:UFSH ratio were compared among different stages of breast development (Table 1) by one-way analysis of variance.
3.3.1 Serum basal Gn, LH peak, and LH:FSH ratio The differences among the three stages were statistically significant (P < 0.05). In particular, the P-value of ULH1, ULH2, total 4-hour ULH, and the ULH:UFSH ratio after the GnRH stimulation test were <0.01.

Serum basal LH, LH peak, LH:FSH ratio, and LH in MU1
The differences between Tanner stage II and the other two stages were statistically significant (P < 0.05). The differences in ULH2, 4-hour ULH, and the ULH:UFSH ratio between Tanner stages II and III were also statistically significant (P < 0.05). The areas under the ROC of the serum peak LH, peak FSH, LH:FSH ratio, total 4-hour ULH, UFSH, and ULH:UFSH ratio were 0.728, 0.427, 0.748, 0.741, 0.399, and 0.741, respectively ( Figure 2). The clinical value was higher for the serum peak LH, serum LH:FSH ratio, and ULH:UFSH ratio in the total 4-hour urinary sample. The serum peak LH cut-off point was 6.2 with a sensitivity of 84.6% and specificity of 59.0%. The serum LH:FSH ratio cut-off point was 0.845 with a sensitivity of 80.8% and specificity of 61.4%. The total 4-hour ULH cut-off point was 5.97 with a sensitivity of 69.2% and specificity of 80.7%. The total 4-hour ULH:UFSH ratio cut-off point was 0.79 with a sensitivity of 65.4% and specificity of 80.7%.

Analysis of ROC curve
The diagnostic criteria for central precious puberty indicate that the serum LH:FSH ratio should be >0.6 after the GnRH stimulation test. The value of UGn1, UGn2, UGn, and the ULH:UFSH ratio in total 4-hour urine in evaluation of a serum LH:FSH ratio of >0.6 was as follows. ULH1, ULH2, 4-hour urinary ULH, and the ULH:UFSH ratio had greater evaluation value, and the areas under the ROC were 0.781, 0.776, 0.779, and 0.812, respectively ( Figure   3), indicating that these indices can help to distinguish premature thelarche and central precious puberty. The ULH1 cut-off point was 1.58 with a sensitivity of 79.4% and specificity of 71.7%. The ULH2 cut-off point was 2.11 with a sensitivity of 71.4% and specificity of 76.1%. The total 4-hour ULH cut-off point was 3.27 with a sensitivity of 82.5% and specificity of 71.7%. The total 4-hour ULH:UFSH ratio cut-off point was 0.49 with a sensitivity of 69.8% and specificity of 84.8%.